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Altered vasculature and the resultant chaotic tumor blood flow lead to the appearance in fast‐growing tumors of regions with gradients of oxygen tension and acute hypoxia (less than 1.4 % oxygen).1 Due to its roles in tumorigenesis and resistance to therapy, hypoxia represents a problem in cancer therapy.1, 2 Insufficient delivery of therapeutic agents to the hypoxic regions in solid tumors is recognized as one of the causes of resistance to therapy.1, 3 This led to the development of hypoxia imaging agents,4 and the use of hypoxia‐activated anticancer prodrugs.2a Here we show the first example of the hypoxia‐induced siRNA uptake and silencing using a nanocarrier consisting of polyethyleneglycol 2000, azobenzene, polyethyleneimine (PEI)(1.8 kDa), and 1,2‐dioleyl‐sn‐glycero‐3‐phosphoethanolamine (DOPE) units (the nanocarrier is referred to as PAPD), where azobenzene imparts hypoxia sensitivity …